1-(4-arylpiperazin-1-yl)-ω-[n-(α..omega.-dicarboximido)]-alkanes useful as uro-selective α1 -adrenoceptor blockers

ABSTRACT

Novel piperzine derivatives substituted on one nitrogen by an aromatic system and on the other nitrogen by (2,5-dioxopyrrolidin)-1-yl) alkanes or (2,6-dioxopiperidin-1-yl) alkanes have been found to exhibit selective α 1A  adrenergic activity. The compounds are useful for treatment of disease conditions, such as peripheral vascular disease, congestive heart failure, hypertension and especially benign prostatic hypertrophy.

This application is a division of U.S. application Ser. No. 09/120,265filed Jul. 21, 1998.

1. FIELD OF THE INVENTION

The present invention relates to certain novel piperazine derivativeshaving protracted uro-selective α₁ -adrenoceptor antagonistic activityexceeding those of previously described compounds. The compounds of thepresent invention hold promise for treating benign prostatic hyperplasia(BPH). This invention also relates to methods for making the novelcompounds, pharmaceutical compositions containing the compounds, andmethods of treating benign prostatic hyperplasia using the compounds.

2. DESCRIPTION OF THE RELATED ART

A review in J. Med. Chem., 1997, V.40, No.9, pp.1291-1315, describes themost important pharmacological options available at present in thetreatment of benign prostatic hyperplasia. The two most successfultherapies are based on α-adrenergic receptor antagonism and androgenlevels modulation by 5α-reductase inhibitors. 5α-reductase inhibitorsare of limited effectiveness in terms of immediate symptomatic andurodynamic relief. α₁ -antagonists appear to be much more effective andprovide immediate subjective symptomatic improvements and are thereforethe preferred modalities of treatment in the control of benign prostatehypertrophy. α₁ -adrenoceptors are also present in blood vessels andplay an important role in the regulation of blood pressure. Thus, α₁-adrenoceptor antagonists are of particular importance as they wereoriginally developed as antihypertensive agents and are likely also tohave a beneficial effect on lipid dysfunction and insulin resistance,which are commonly associated with essential hypertension.

The more important of the α₁ -adrenoceptor antagonists which arecurrently used in the management of BPH are shown below. ##STR1##

However, most of these known drugs are associated with vascular sideeffects (e.g., postural hypertension, syncope, dizziness, headaches,etc.) due to lack of selectivity of action between prostatic andvascular α₁ -adrenoceptors. Clearly, α₁ -adrenoceptor antagonists whichhave inherently greater selectivity for prostatic α₁ -adrenoceptorsoffer the potential of increased urodynamic benefits. This underscoresthe importance of the discovery of prostate-selective α₁ -adrenoceptorantagonists which will confer urodynamic improvement without the sideeffects associated with existing drugs.

Recently, it has been demonstrated that the prostate tissue of higherspecies like man and dog is overvalued by low affinity α_(1A)-adrenoceptor subtype. This makes it possible to develop agents withselective action against these pathological urodynamic states. Thepresent invention is directed to the development of novel α₁-antagonists, namely, a new class of piperazine compounds, with greaterselectivity of action against α_(1A) -adrenoceptors and which would thusoffer selective relief for prostate hypertrophy as well as essentialhypertension.

There are many descriptions in the literature of the pharmacologicalactivities associated with phenyl piperazines. Eur. J. Med.Chem.-Chimica Therapeutica, 1977, V. 12, No. 2, pp. 173-176, describessubstituted the trifluoromethyl phenyl piperazines having cyclo-imidoalkyl side chains shown below as anorectic agents with no CNS sideeffects. ##STR2##

The synthesis and pharmacology of some2-[3-(4-aryl-1-piperazinyl)propyl]-1H-benz[de]isoquinolin-1,3-(2H)-diones/2,5-pyrrolidinediones(J. Indian Chem. Soc., 1986, V. LXIII, pp. 529-530), of N-(N⁴ -aryl-N¹-piperozinylmethyl)-4-(4'-methoxyphenyl)piperidine-2,6-diones (J. IndianChem. Soc., 1978, v. LV, pp. 819-821), and of N-(N⁴-arylpiperazinylalkyl)-phthalimides (J. Indian Chem. Soc., 1979, V. LVI,pp. 1002-1005), as shown below, have been reported. The compounds wereshown to exhibit antihypertensive and CNS depressant activity inexperimental animals. ##STR3##

However, in those papers there is no mention of the adrenoceptorblocking activity of these compounds, and thus their usefulness in thetreatment of benign prostate hyperplasia did not arise.

The earlier synthesis of various1-(4-aryl-piperazin-1-yl)-3-(2-oxo-pyrrolidin-1-yl/piperidin-1-yl)alkanes and their usefulness as hypotensive and antischemic agents isdisclosed in unpublished Indian patent applications DEL 496/95 (Mar. 3,1995), DEL/500/95 (Mar. 21, 1995) and DEL/96/96 (Mar. 29, 1996) by theinventors herein. These compounds had low α₁ -adrenergic blockingactivity (pKi˜6 as compared to >8 of the known α₁ -antagonists such asprazosin), and practically no adrenoceptor sub-class selectivity forα_(1A) vs. α_(1B) or α_(1D) adrenoceptors. It has now been discoveredthat structural modification of these compounds from lactam to dioxocompounds, i.e., from 2-oxopyrrolidin to 2,5-dioxopyrrolidin and2,6-dioxopiperidine, enhances the adrenoceptor blocking activity, andalso greatly increases the selectivity for α_(1A) in comparison toα_(1B) -adrenoceptor blocking activity, an essential requirement forcompounds to be good candidates for treatment of BPH.

3. OBJECTS OF THE INVENTION

An object of the present invention, therefore, is to provide novelarylpiperazine derivatives that exhibit significantly greater α_(1A)-adrenergic blocking potency than available with the known compounds inorder to provide specific treatment for benign prostatic hyperplasia.

It is also an object of the invention to provide a method for synthesisof the novel compounds.

It is a further object of the invention to provide compositionscontaining the novel compounds which are useful in the treatment ofbenign prostatic hyperplasia.

4. SUMMARY OF THE INVENTION

The above-mentioned objectives are achieved by a novel class ofpiperazine derivatives of general Formula I below ##STR4## wherein Y isO or S; Q, X, Z and Z' are independently CH or N; m=0-3; n=0-4; R₁, R₂are independently selected from: H, F, Cl, Br, OCH₃, OC₂ H₅, OCH₂ CF₃,SCH₃, CH₃, C₂ H₅, CF₃, isopropyloxy, and cyclopropyl; R₃ is H, R₆, OH orOR₆ ; R₆ is a substituted or unsubstituted alkyl chain containing 1-6carbon atoms; and R₄, R₅ are H, C₁₋₃ alkyl, substituted or unsubstitutedphenyl, or a 5-membered spiro ring. Preferably, R₁ is H, R₂ is H, Cl orCF₃, R₃, R₄, and R₅ =H, Y═O and Q═CH when m=0 and n=1; or R₁ is H, R₂ isOCH₃, R₃, R₄ and R₅ =H, Y═O and Q═CH when m=0 and n=2.

Compounds within the scope of Formula I but having the structure ofFormula II below ##STR5## wherein n, X, Z Z' R'₁, R₂ and R₃ are asdefined for Formula I, and wherein m'=1-4, are preferred as selectiveand potent α_(1A) -adrenoceptor antagonistic activity over the α_(1B) -and α_(1D) -adrenoceptors. In Formula II, preferably R₁ is H, R₂ is H,Cl or CF₃, and R₃ is H when m'=1 and n=1; or R₁ is H, R₂ is OCH₃, and R₃is H when m'=1 and n=2.

The present invention also provides pharmaceutical compositions for thetreatment of benign prostatic hyperplasia. These compositions comprisean effective amount of at least one of the above compounds of Formula I,or preferably of Formula II, and/or an effective amount of at least onephysiologically acceptable acid addition salt thereof, with apharmaceutically acceptable carrier.

An illustrative list of particular compounds of the invention is givenbelow:

    __________________________________________________________________________    Compound                                                                      No.   Chemical Name                                                           __________________________________________________________________________     1.   1-[4-(4-Fluorophenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)pro          pane                                                                     2.   1-[4-(2-Methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)pr          opane                                                                    3.   1-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin          -1-yl)propane                                                            4.   1-[4-(2-Pyridyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane      5.   1-[4-(3-Chlorophenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)pro          pane                                                                     6.   1-[4-(2-Pyrimidyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propan          e                                                                        7.   1-[4-(3,4-Dimethylphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl          )propane                                                                 8.   1-[4-(Phenylpiperazin)-1-yl]-3-(2,5-dioxopyrrolin-1-yl)propane           9.   1-[4-(2-Methoxyphenyl)piperazin-1-yl]-4-(2,5-dioxopyrrolidin-1-yl)bu          tane                                                                    10.   1-[4-(2-Methoxyphenyl)piperazin-1-yl]-2-(2,5-dioxopyrrolidin-1-yl)et          hane                                                                    11.   1-[4-(3-Methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)pr          opane                                                                   12.   1-[4-(4-Methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)pr          opane                                                                   13.   1-[4-(2-Methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)pro          pane                                                                    14.   1-[4-(4-Fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)prop          ane                                                                     15.   1-[4-(4-Chlorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)prop          ane                                                                     16.   1-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-          1-yl)propane                                                            17.   1-[4-(2-Fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)prop          ane                                                                     18.   1-[4-(2-Methylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)prop          ane                                                                     19.   1-[4-(2-Pyridyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane      20.   1-[4-(3-Chlorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)prop          ane                                                                     21.   1-[4-(3,4-Dimethylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)          propane                                                                 22.   1-[4-(2-Pyrimidyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane    23.   1-[4-(3-Methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)pro          pane                                                                    24.   1-[4-(4-Methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)pro          pane                                                                    25.   1-[4-(2-Methoxyphenyl)piperazin-1-yl]-4-(2,6-dioxopiperidin-1-yl)but          ane                                                                     26.   1-[4-(2-Methoxyphenyl)piperazin-1-yl]-3-[2,5-dioxo-3-phenyl-pyrolidi          n-1-                                                                          yl]propane                                                              27.   1-[4-(Phenyl)piperazin-1-yl]-3-[2,5-dioxopiperidin-1-yl]propane         __________________________________________________________________________

5. DETAILED DESCRIPTION OF THE INVENTION 5a. Synthesis of the Compoundsof the Invention

The compounds of the present invention may be prepared by one of thereaction sequences (Schemes I, II & III) shown below to yield compoundsof Formula II with the R₁, R₂, R₃, R₄, R₅, R₆, m, n, Z, Z', Q and Ygroups as defined above. The starting materials for Schemes I, II andIII may be suitably adapted to produce the more general compounds ofFormula I.

Scheme--I

Scheme-I shows the synthesis of compounds of the Formula II in which R₁,R₂, R₃, R₄, R₅, R₆, m', n, Z, Z', Q, X, and Y are as defined earlier.The preparation comprises condensing α,ω-dicarboximides of Formula IIIwith 1-(4-arylpiperazin-1-yl)-ω-chloroalkanes of Formula IV, in thepresence of a base and an organic solvent at a temperature ranging from80-150° C. for a period varying between 8-24 hours to produce thecorresponding 1-(4-arylpiperazin-1-yl)-ω-[N-(α,ω-dicarboximido)]alkanesof the Formula II where R₁ and R₂ have the meanings given above. Phasetransfer catalysts, preferably tetrabutylammonium bromide, areparticularly useful in catalysing the reaction. ##STR6## Scheme--II

The compounds of Formula II can also be prepared by condensation of thepiperazines of the Formula V with the anhydrides of Formula VI whereinR₁, R₂, R₃, Y, Z, Z', X, and m' are as defined above. ##STR7##Scheme--III

The compounds of Formula II can also be prepared by alkylation of theα,ω-dicarboximide moiety with α,ω-dihaloalkanes followed by condensationof 1-(ω-haloalkyl)dicarboximide thus obtained (Formula VII) with1-arylpiperazines (Formula VIII) as shown below, wherein R₁, R₂, R₃, Y,Z, Z', X, m' and n are as defined above. The reaction is preferablycarried out in the presence of a base and an organic solvent at atemperature ranging from 60-100° C. for a period varying between 10-24hours to produce the corresponding1-(4-arylpiperazin-1-yl)-ω-[N-(α,ω-dicarboximido)]alkanes of Formula II.Phase transfer catalysts, more preferably tetrabutylammonium bromide andpotassium iodide, are useful in catalysing the reaction. ##STR8##

In the above Schemes, where specific bases, acids, solvents, phasetransfer catalysts, etc., are mentioned, it is to be understood thatother acids, bases, solvents, phase transfer catalysts, etc., known tothose skilled in the art may also be used. Similarly, the reactiontemperature and duration of the reactions may be adjusted according tothe desired needs.

The starting piperazines of the Formulas IV, V and VIII are known in theart and may be synthesized by the procedures described in Kiritzy, J.A., et al., J. Med. Chem., 1978, V. 21, p. 1301; U.S. Pat. No. 3,637,705(Abbott, 1972); FR 2,179,491 (1973); Aggarwal S. K., et al., Ind. J.Chem., 1982, V.21B, pp. 435-439; and U.S. Pat. No. 2,922,788 (Parcell,1960).

5b. Pharmacological Testing Results

The affinity of the compounds of the invention for each subtype ofα-adrenoceptor can be assessed by receptor binding assays (RBA's)described in the examples given below. It should be noted that theidentification and characterization of the foregoing receptors is stillin progress and that their types and subtypes are subject to review andrefinement.

Receptor binding and in vitro functional assay studies described belowindicated that the compounds of the present invention possess selectiveand potent α_(1A) adrenoceptor antagonistic activity over the α_(1B) andα_(1D) adrenoceptors. The present invention also provides a method todemonstrate the selective affinity of the compounds for prostatictissues over vascular tissues. Further, the examples presented belowdescribe a method to treat BPH in mammals wherein the test compoundsalleviated pressure at dosages which did not result in significantchange in blood pressure. Several of the compounds of present inventiondemonstrated manifest selectivity for prostatic tissues in comparison toknown compounds, such as terazosin, doxazosin, etc. The compounds of thepresent invention also lowered the blood pressure with prolongedduration of action. The compounds of the present invention have beendemonstrated to be useful for treating warm blooded animals and mammals.These compounds can be administered orally or parenterally in suitablepharmaceutical compositions.

Preferred compounds of the invention are1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane(Compound No. 2),1-[4-(2-methoxyphenyl)piperazin-1-yl]-4-(2,5-dioxopyrrolidin-1-yl)butane(Compound No. 9), and1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane(Compound No. 13).

Pharmaceutically acceptable, non-toxic, acid addition salts of thecompounds of the present invention having the utility of the free basesof Formulas I and II may be formed with inorganic or organic acids, bymethods well known in the art and may be used in place of the freebases. Representative examples of suitable acids for formation of suchacid addition salts are malic, fumaric, benzoic, ascorbic, pamoic,succinic, bismethylene salicylic, methanesulfonic, ethane disulfonic,acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfamic, phosphoric, hydrobromic, sulfuric, cyclohexylsulfamic,hydrochloric and nitric acids.

The present invention also includes within its scope prodrugs of thecompounds of Formulas I and II. In general, such prodrugs will befunctional derivatives of these compounds which are readily converted invivo into the defined compounds. Conventional procedures for theselection and preparation of suitable prodrugs are known.

The invention also includes the enantiomers, diasteromers, N-oxides andpharmaceutically acceptable salts of these compounds, as well asmetabolites having the same type of activity. The invention furtherincludes pharmaceutical compositions comprising the molecules of FormulaI and II, or prodrugs, metabolites, enantiomers, diasteromers, N-oxides,or pharmaceutically acceptable salts thereof, in combination with apharmaceutically acceptable carrier and optionally included excipients.

In yet another aspect, the invention is directed to methods forselectively blocking α_(1A) receptors by delivering in the environmentof said receptors, e.g., to the extracellular medium (or byadministering to a mammal possessing said receptors), an effectiveamount of the compounds of the invention.

The invention will now be illustrated by the following non-limitingexamples.

Preparation of1-[4-(4-Fluorophenyl)piperazin-1-yl]-3-[2,5-dioxopyrrolidin-1-yl]propane(Compound No. 1)

Scheme-I: A mixture of 2,5-dioxopyrrolidine (0.500 g, 5 mmol),1-[4-(4-fluorophenyl)-piperazin-1-yl]-3-chloropropane (1.28 g, 5 mmol),potassium carbonate (0.502 g, 3.75 mmol) and tetrabutylammonium bromide(0.322 g, 1 mmol) in acetone (25 ml) was refluxed for 16 hours at 80° C.with stirring. The solvent was evaporated off in vacuo and the residuewas suspended in water (80 ml). The aqueous solution was extracted withchloroform (3×50 ml), and the organic layers combined, washed with water(2×50 ml), dried over Na₂ SO₄ and evaporated in vacuo to give the titlecompound. The product was purified by column chromatography over flashsilica gel using chloroform-methanol (98:2) as eluent; yield 1.00 g(65%), oil.

Scheme-II: 1-amino-3-[4-(4-fluorophenyl)piperazin-1-yl]propane (0.700 g,2.95 mmol) and succinic anhydride (0.295 g, 2.95 mmol) were refluxed inpyridine (10 ml) for 10 hours. Acetic anhydride (2 ml, excess) was addedand the mixture was further refluxed for 5 hours. Solvent was remove dinvacuo and the residue was suspended in water and extracted withchloroform (2×25 ml). Organic layers were combined, washed with water(2×25 ml), dried over Na₂ SO₄ and concentrated. The compound waspurified by column chromatography over flash silica gel usingchloroform-methanol (98:2) as eluent; yield 0.436 g (46%), oil.

Scheme-III: A mixture of 1-chloro-3-(2,5-dioxopyrrolidin-1-yl) propane(1.54 g, 8.80 mmol), 1-(4-fluorophenyl)piperazine (1.58 g, 8.80 mmol),potassium carbonate (1.21 g, 8.80 mmol) and potassium iodide (0.146 g,0.88 mmol) in N,N-dimethylformamide (25 ml) was heated at 100° C. for 18hours. Solvent was evaporated under reduced pressure. Residue was shakenwith water (25 ml), extracted with chloroform (2×25 ml), and the organiclayers combined, washed with water (2×20 ml), dried over Na₂ SO₄ andconcentrated to give an oil which was purified by column chromatographyover flash silica gel using chloroform-methanol (98:2) as eluent; yield2.00 g (71%), oil.

The hydrochloride salt of1-[4-(4-fluorophenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)-propane(Compound No. 1) was formed in quantitative yield by the addition ofethereal hydrogen chloride solution to a methanolic solution of the freebase and the resultant precipitate was collected by filtration; m.p.246-247° C.

Preparation of1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-[2,5-dioxopyrrolidin-1-yl]propane(Compound No. 2)

Scheme-I: A mixture of 2,5-dioxopyrrolidine (3.68 g, 37.24 mmol),1-[4-(2-methoxyphenyl)-piperazin-1-yl]-3-chloropropane (10.0 g, 37.24mmol), potassium carbonate (7.70 g, 55.8 mmol) and tetrabutylammoniumbromide (2.38 g, 7.4 mmol) in acetone (100 ml) was refluxed for 12 hoursat 80° C. with stirring. The solvent was evaporated off in vacuo and theresidue was taken up in water (80 ml). The aqueous solution wasextracted with chloroform (3×50 ml) and the organic layers combined,washed with water 2×50 ml), dried over Na₂ SO₄ and evaporated in vacuoto give the title compound. The product was purified by columnchromatography over flash silica gel using chloroform-methanol (99:1) aseluent; yield 8.00 g (65%) in oil. The hydrochloride salt was preparedby the method described above; mp 199-202° C.

Scheme-III: A mixture of 1-chloro-3-(2,5-dioxopyrrolidin-1-yl) propane(28.00 gm, 159.5 mmol), 1-(2-methoxyphenyl)piperazin hydrochloride(36.45 g, 159.5 mmol), potassium carbonate (44.03 g, 319.0 mmol) andpotassium iodide (1.58 g, 9.57 mmol) in N,N-dimethylformamide (115 ml)was heated at 80° C. for 17 hours and the solvent was evaporated underreduced pressure. Residue was suspended in ethyl acetate (600 ml),washed with water (5×100 ml.) and dried over Na₂ SO₄ and concentrated togive an oil which was purified by column chromatography over silica gel(100-200 mesh) using chloroform-methanol (99:2) as eluent; yield 55.1 g,(80%), oil. The hydrochloride salt of this product was formed in themanner described above; mp. 199-202° C.

1-Chloro-3-(2,5-dioxopyrrolidin-1-yl)propane can be prepared by thereaction of 2,5-dioxopyrrolidine and 1-bromo-3-chloropropane in thepresence of potassium carbonate and tetrabutylammonium bromide inacetone.

Preparation of1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-[2,5-dioxopyrrolidin-1-yl]butane(Compound No. 9)

Scheme-III: A mixture of 1-chloro-4-(2,5-dioxopyrrolidin-1-yl)butane(11.0 g, 58.04 mmol), 1-[2-methoxyphenyl)piperazin hydrochloride (12.99g, 56.85 mmol), potassium carbonate (16.02 g, 116.09 mmol) and potassiumiodide (0.577 g, 3.48 mmol) in N,N-dimethylformamide (45 ml) was stirredat 100° C. for 18 hours. N,N-dimethylformamide was evaporated at reducedpressure and the residue was taken up in water (100 ml) and extractedwith chloroform (2×100 ml). The extracts were dried over Na₂ SO₄ andconcentrated under reduced pressure to give1-[4-(2-methoxyphenyl)piperazine-1-yl]-4-(2,5-dioxopyrrolidin-1-yl)butaneas an oil which was purified by column chromatography over silica gel(230-400 mesh) using chloroform-methanol (98.2) as eluent; yield 18.00g, (92%), oil. Hydrochloride salt was prepared by the method describedabove; mp 218-220° C.

1-Chloro-4-(2,5-dioxopyrrolidin-1-yl)butane can be prepared by thereaction of 2,5-dioxopyrrolidine and 1-bromo-4-chlorobutane in thepresence of potassium carbonate and tetrabutylammonium bromide inacetone.

Preparation of1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-[2,6-dioxopiperidin-1-yl)propane(Compound No. 13)

Scheme-I: A mixture of 2,6-dioxopiperidine (2.60 g, 23.02 mmol),1-[4-(2-methoxyphenyl)-piperazin-1-yl]-3-chloropropane (6.18 g, 23.02mmol), potassium carbonate (2.38 g, 17.27 mmol) and tetrabutylammoniumbromide (1.48 g, 4.60 mmol) in acetone (80 ml) was refluxed for 16 hoursat 80° C. with stirring. The solvent was evaporated off in vacuo and theresidue suspended in water (60 ml), extracted with chloroform (3×40mmol) and the organic layers combined, washed with water (2.40 ml),dried over anhydrous Na₂ SO₄ and evaporated in vacuo to give the titlecompound. The product was purified by column chromatography over flashsilica gel (230-400 mesh) using chloroform-methanol (98:1) as eluent;yield 3.58 g (45%), oil.

The hydrochloride salt was prepared in the quantitative yield by themethod described above; m.p. 206-210° C.

Scheme-III: A mixture of 1-chloro-3-(2,6-dioxopiperidin-1-yl)propane(22.06 gm, 116.40 mmol), 1-(2-methoxyphenyl)piperazine (21.90 g, 114.06mmol), potassium carbonate (16.06 g, 116.40 mmol) and potassium iodide(1.16 g, 6.98 mmol) in N,N-dimethylformamide (90 ml), was heated at 80°C. for 17 hrs. and the solvent was evaporated under reduced pressure.Residue was dissolved in ethyl acetate (400 ml), washed with water(5×100 ml) and dried over Na₂ SO₄ and concentrated to given an oil whichwas purified by column chromatography over silica gel (100-200 mesh)using chloroform-methanol (99:1) as eluent; yield 33.8 g, (86%), oil.The hydrochloride salt was prepared in the quantitative yield by theaddition of excess ethereal hydrogen chloride solution to a methanolicsolution of the free base and collected by filtration of the resultantprecipitate; m.p. 206-210° C.

An illustrative list of the compounds of the invention which weresynthesized by one or more of the above described methods is now given.

1-[4-(4-Fluorophenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propanehydrochloride; m.p. 246-247° C.

1-[4-(2-Methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propanehydrochloride; m.p. 199-202° C.

1-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propanehydrochloride; m.p. 218-220° C.

1-[4-(2-Pyridyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propanehydrochloride; m.p. 261-262° C.

1-[4-(3-Chlorophenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propanehydrochloride; m.p. 230-231° C.

1-[4-(2-Pyrimidyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propanehydrochloride; m.p. 196-198° C.

1-[4-(3,4-Dimethylphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane hydrochloride; m.p. 244-246° C.

1-[4-(Phenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propanehydrochloride; m.p. 258-259° C.

1-[4-(2-Methoxyphenyl)piperazin-1-yl]-4-(2,5-dioxopyrrolidin-1-yl)butanehydrochloride; m.p. 219-220° C.

1-[4-(2-Methoxyphenyl)piperazin-1-yl]-2-(2,5-dioxopyrrolidin-1-yl)ethanehydrochloride; m.p. 232-234° C.

1-[4-(3-Methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propanehydrochloride; m.p. 199-201° C.

1-[4-(4-Methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propanehydrochloride; m.p. 240-242° C.

1-[4-(2-Methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)-propanehydrochloride; m.p. 206-210° C.

1-[4-(4-Fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane;m.p. 200-202° C.

1-[4-(4-Chlorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propanehydrochloride; m.p. 206-208° C.

1-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propanehydrochloride; m.p. 228-229° C.

1-[4-(2-Fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propanehydrochloride; m.p. 215-216° C.

1-[4-(2-Methylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propanehydrochloride; m.p. 206-207° C.

1-[4-(2-Pyridyl)piperazin-1-yl)-3-(2,6-dioxopiperidin-1-yl)propanehydrochloride; m.p. 244-245° C.

1-[4-(3-Chlorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propanehydrochloride; m.p. 214-215° C.

1-[4-(3,4-Dimethylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propanehydrochloride; low melting hygroscopic.

1-[4-(2-Pyrimidyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propanehydrochloride; m.p. 195-196° C.

1-[4-(3-Methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propanehydrochloride; m.p. 196-197° C.

1-[4-(4-Methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propanehydrochloride; m.p. 218-220° C.

1-[4-(2-Methoxyphenyl)piperazin-1-yl]-4-(2,6-dioxopiperidin-1-yl)butanehydrochloride; m.p. 190-192° C.

1-[4-(2-Methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxo-3-phenylpyrrolidin-1-yl]propanehydrochloride; m.p. 171-172° C.

1-[4-(Phenyl)piperadin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl]propanehydrochloride; m.p. 208-209° C.

All the melting points reported above are uncorrected and measured by anopen capillary method using Buchi 535.

Receptor Binding Assay

In vitro receptor binding

Receptor binding assays (RBA's) were performed for native α₁-adrenoceptors. Rat submaxillary and rat liver membrane preparationswere used to assess the affinity for α_(1A) and α_(1B) subtypes,respectively. Aliquots of membrane protein (100-200 mg) were incubatedin a final volume of 250 ml assay buffer (50 mM Tris, 0.5 mM EDTA at pH7.4) with 0.5 nM [³ H] prazosin for 60 mins at 28° C. Reaction wasstopped by rapid filtration on Millipore filters. Filters were dried andbound radioactivity counted. Non-specific binding was determined in thepresence of 0.3 mM prazosin. Protein was assayed according to the methodof protein estimation by Lowry, O. H. et al., J. Biol. Chem., V. 193,pp. 265-275 (1951). Results are listed in Table 1.

                                      TABLE 1                                     __________________________________________________________________________                    In Vitro                                                             RBA      Functional                                                           (Ki      Assay      In Vivo BP                                         Compound                                                                             nM)      (pK.sub.B) Fall in                                                                             Duration in                                  No.    .sup.α 1A                                                                    .sup.α 1B                                                                   .sup.α 1A                                                                    .sup.α 1B                                                                  .sup.α 1D                                                                  mmHg  min.                                         __________________________________________________________________________    Compound 1                                                                           >2500                                                                              1000                                                                              7.1  7.0                                                                              6.8                                                                                5.0  15.0                                        Compound 2                                                                            19   244                                                                              8.7  7.6                                                                              7.3                                                                              25    120.0                                        Compound 3                                                                           1500 1000                                                                              --   7.2                                                                              5.0                                                                              --    --                                           Compound 4                                                                           1660 2100                                                                              --   -- 5.6                                                                              --    --                                           Compound 5                                                                            106  175                                                                              5.3  5.3                                                                              7.0                                                                              --    --                                           Compound 6                                                                           1140 >2500                                                                             4.7  5.3                                                                              6.5                                                                              --    --                                           Compound 7                                                                            450  282                                                                              6.4  6.7                                                                              6.5                                                                              --    --                                           Compound 8                                                                            57   590                                                                              7.5  -- 6.6                                                                              --    --                                           Compound 9                                                                             1   35 9.0  8.0                                                                              8.3                                                                              46    >180                                         Compound 10                                                                          1600 2350                                                                              6.9  6.7                                                                              6.9                                                                              --    --                                           Compound 11                                                                          >2500                                                                              >2500                                                                             --   -- -- --    --                                           Compound 12                                                                          >2500                                                                              >2500                                                                             --   -- -- --    --                                           Compound 13                                                                            3   168                                                                              8.6  8.0                                                                              7.9                                                                              50.0  >180                                         Compound 14                                                                           67   192                                                                              8.4  7.4                                                                              7.1                                                                              20.0   60.0                                        Compound 15                                                                           520  201                                                                              6.7  6.0                                                                              6.2                                                                              --    --                                           Compound 16                                                                           345  765                                                                              6.5  -- 6.9                                                                              --    --                                           Compound 17                                                                           21   396                                                                              8.0  7.1                                                                              7.9                                                                              50.0  120.0                                        Compound 18                                                                            9   267                                                                              8.2  5.5                                                                              8.5                                                                              40.0  >150                                         Compound 19                                                                           164 >2500                                                                             6.4  -- 6.7                                                                              --    --                                           Compound 20                                                                           22   113                                                                              7.5  -- 7.6                                                                              --    --                                           Compound 21                                                                          2130  176                                                                              6.5  6.7                                                                              6.5                                                                              --    --                                           Compound 22                                                                          >2500                                                                              >2500                                                                             6.4  -- 7.0                                                                              --    --                                           Compound 23                                                                          2170  940                                                                              --   -- -- --    --                                           Compound 24                                                                          <2500                                                                              >2500                                                                             --   -- -- --    --                                           Compound 25                                                                             1.6                                                                                7.5                                                                            --   -- -- --    --                                           Compound 26                                                                           30   600                                                                              --   -- -- --    --                                           Compound 27                                                                          1300 2000                                                                              --   -- -- --    --                                           __________________________________________________________________________

In vitro Functional Studies

In vitro α₁ -Adrenoceptor selectivity

In order to study selectivity of action of the present compounds towardsdifferent α-adrenoceptor subtypes, the ability of these compounds toantagonize α₁ -adrenoceptor agonist induced contractile response ofaorta (α_(1D)), prostate (α_(1A)) and spleen (α_(1B)) was studied.Aorta, prostate and spleen tissues were isolated from urethaneanaesthetized (1.5 gm/kg) male wistar rats. Isolated tissues weremounted in organ bath containing Krebs Henseleit buffer of the followingcomposition (mM): NaCl 118; KCl 4.7; CaCl₂ 2.5; MgSO₄.7H₂ O 1.2; NaHCO₃25; KH₂ PO₄ 1.2; glucose 11.5. Buffer was maintained at 37° C. andaerated with a mixture of 95% O₂ and 5% CO₂. A resting tension of 2 g(aorta) or 1 g (spleen and prostate) was applied to tissues. Contractileresponse was monitored using a force displacement transducer andrecorded on chart recorders. Tissues were allowed to equilibrate for 2hours. At the end of equilibration period, concentration response curvesto norepinephrine (aorta) and phenylephrine (spleen and prostate) wereobtained in the absence and presence of the tested compound (atconcentrations of 0.1, 1 and 10 μM). Antagonist affinity was calculatedand expressed as pK_(B) values in Table 1.

In vitro Receptor Selectivity

Selectivity of action of the present compounds was tested against arange of different receptors, e.g., β₁ - and α₂ -adrenergic, muscariniccholinergic, serotoninergic (5-HT_(2A)), histaminergic (H₁), angiotensinII, endothelin (ET_(A) and _(B),), as well as calcium and potassiumchannels. Rat aorta was used to study the effect of the compounds on5-HT_(2A), ET_(A), calcium and potassium channels. Angiotensin IIreceptor antagonistic activity was studied in rabbit aorta. Muscariniccholinergic receptor and ET_(B) receptor antagonistic activity wasstudied in rat trachea, while guinea pig trachea was used to study H₁receptor antagonistic activity. Electrically stimulated rat vas deferenswas used to investigate the effect of α₂ -adrenoceptors, while β₁-adrenoceptor antagonistic activity was studied using electricallystimulated rat ventricular strips. Results of this selectivity study isshown in (Table 2).

                  TABLE 2                                                         ______________________________________                                        Selectivity Study                                                             Receptor Type pK.sub.B                                                                 Compound 2                                                                              Compound 9                                                                              Compound 13                                      ______________________________________                                        α.sub.2 -adrenergic                                                                NE          NE        NE                                           β-adrenergic                                                                        4.2         --        5.1                                          Muscarinic 5.0         5.0       5.5                                          H.sub.1 -Histaminergic                                                                   5.3         5.4       5.7                                          5-HT.sub.2A                                                                              7.6         7.9       8.0                                          ET.sub.A   --          4.3       4.3                                          ET.sub.B   --          5.4       4.9                                          Angiotensin II                                                                           --          5.6       5.3                                          Calcium Channel                                                                          NE          NE        NE                                           Potassium Channel                                                                        NE          NE        5                                            ______________________________________                                         NE: No effect                                                                 (--): Not tested                                                         

In vivo Antihypertensive Effect

Antihypertensive effect of selected compounds according to the inventionwere studied for their ability to lower blood pressure in anaesthetizedand conscious normotensive and spontaneously hypertensive rats viaintravenous, oral and intraduodenal routes. Results are shown in Tables1 and 3.

Anaesthetized Normotensive Rats

Intravenous Route

Male wistar rats were anasthetized with urethane (2.5 g/kg). Femoralvein and carotid artery were cannulated. Blood pressure and heart ratewere recorded using Statham pressure transducer. Data was recorded onGrass polygraph as well as using online data acquisition system (BuxcoAT). Intravenously administered compounds of the invention wereinitially tested at 0.3 mg/kg over a period of 3 hours for their effecton blood pressure and the results are shown in Table 1. For a select fewof the compounds, the blood pressure lowering effect upon intravenousadministration was also studied at dosages of 0.03, 0.1, 0.3, and 1mg/kg.

Intraduodenal Route

Male wistar rats were fasted for 18 hours. Rats were anaesthetized withurethane. Femoral vein and carotid artery were cannulated. A catheterwas placed in the duodenum following lapratomy. The compounds of thepresent invention (at dosages of 0.3, 1, 3 and 10 mg/kg) wereadministered in the duodenum and blood pressure was monitored for 3hours. Results are recorded in Table 3.

                  TABLE 3                                                         ______________________________________                                        Effect on mean arterial pressure in                                           anaesthetized normotensive rats.                                                                    Mean Arterial                                                                 Pressure                                                           Dose       (% Change  Duration                                     Compound No.                                                                             (mg/kg)    from basal)                                                                              of Action                                    ______________________________________                                        Compound 2 1          -19        >2.5 hr                                                 3          -43        >2.5 hr                                                 10         -42        >2.5 hr                                      Compound 9 1          -19        >3.0 hr                                                 3          -53        >3.0 hr                                                 10         -57        >3.0 hr                                      Compound 13                                                                              1          -32        <3.0 hr                                                 3          -40        >3.0 hr                                                 10         -42        >3.0 hr                                      ______________________________________                                    

Conscious Normotensive Rats

Femoral artery of normotensive male wistar rats, maintained on anovernight light diet, were catheterized under pentobarbitone anaesthesia(35 mg/kg). Femoral artery catheter was exteriorized through the neckregion for blood pressure recording. Compounds of the present invention(at dosages of 0.1, 0.3 and 1 mg/kg) were administered 24 hoursfollowing surgery through oral route in the form of gavage to overnightfasted rats. Blood pressure and heart rate were recorded with the helpof Statham pressure transducer on a Grass polygraph and the results areshown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Effect on systolic blood pressure in                                          conscious spontaneously hypertensive rats                                                           Systolic Pressure                                                     Dose    (% Change from basal)                                   Compound No.  (mg/kg) (at 6 hours)                                            ______________________________________                                        Compound 2     1      -7.0                                                                   3      -12.0                                                                 10      -13.0                                                                 30      -17.0                                                   Compound 9     1      -0.4                                                                   3      -7.0                                                                  10      -24.0                                                                 30      -25.0                                                   Compound 13    1      -7.0                                                                   3      -18.0                                                                 10      -19.0                                                                 30      -14.0                                                   ______________________________________                                    

Conscious Spontaneously Hypertensive Rats

Spontaneously hypertensive rats weighing between 250-300 g were used inthis study. Rats were fasted overnight. Blood pressure was monitoredfrom tail artery using semi-automatic noninvasive blood pressuremonitoring apparatus. Compounds of the present invention (at dosages of1, 3, 10, and 30 mg/kg) were administered orally. Blood pressure wasmonitored prior to and 1.5, 4, 6 and 24 hours after drug administration.Results are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                        Effect on mean arterial blood pressure in                                     conscious freely moving normotensive rats.                                                  Dose    Mean Arterial Pressure                                  Compound No.  (mg/kg) (% Change from basal)                                   ______________________________________                                        Compound 2    3       -14                                                                   10      -10                                                     Compound 9    1        -4                                                                   10      -11                                                     Compound 13   1        -5                                                                   3       -10                                                     ______________________________________                                    

In Vivo Selectivity Study

Male mongrel dogs (12-20 Kg) were anaesthetized with pentobarbitonesodium (35 mg/kg, iv). Trachea was incubated for artificial respiration.Femoral artery and femoral vein were cannulated for recording bloodpressure and for administration of drug solutions, respectively. Bloodpressure was recorded on a polygraph through a pressure transducer. Aparamedian incision was made lateral to the penis and the bladder wasexposed. Urine was drained through a cannula put directly into thebladder and it was guided into the urethra gently and was placed at theprostatic urethra. Balloon was inflated with 2 cc air and its placementwas confirmed by digital pressure. Intraurethral pressure was recordedon the polygraph through a pressure transducer. Graded dose responserelationship of phenylephrine (1-16 μg/kg, iv) was obtained on prostaticpressure and blood pressure, prior to administration of the compounds ofthe present invention. Compounds 2, 9, and 13 (at dosages of 0.01, 0.03,0.1, and 0.3 mg/kg) were administered intravenously 10 min beforeobtaining phenylephrine dose response curves. Results were analyzed andpseudo pK_(B) values were calculated as described in Kenny et al (1996).Results are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                        Effect on blood pressure and                                                  intraurethral pressure in anaesthetized dogs                                  pseudo pK.sub.B                                                                          Blood Pressure                                                                         Intraurethral Pressure                                    ______________________________________                                        Compound 2   6.9         7.60                                                 Compound 9   7.4        7.9                                                   Compound 13  7.1        8.1                                                   ______________________________________                                    

While the invention has been described by reference to specificembodiments, this was for purposes of illustration only. Numerousalternative embodiments will be apparent to those skilled in the art andare deemed to be within the scope of the invention.

What is claimed is:
 1. The compound which is1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propaneor its hydrochloride salt.
 2. The compound which is1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propaneor its hydrochloride salt.
 3. The compound which is1-[4-(2-fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propaneor its hydrochloride salt.
 4. The compound which is1-[4-(2-methylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propaneor its hydrochloride salt.
 5. The compound which is1-[4-(2-pyridyl)piperazin-1-yl)-3-(2,6-dioxopiperidin-1-yl)propane orits hydrochloride salt.
 6. The compound which is1-[4-(2-Methoxyphenyl)piperazin-1-yl]-3-[2,5-dioxo-3-phenyl-pyrolidin-1-yl]propaneor its hydrochloride salt.
 7. The compound which is1-[4-(Phenyl)piperidin-1-yl]-3-[2,5-dioxopyrolidin-1-yl]propane or itshydrochloride salt.
 8. A pharmaceutical composition comprising thecompound of any of claims 1, 2, 3, 4, 5, 6, or 7 pharmaceuticallyacceptable carrier.